Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pulmonary chemoreflexes evoked by phenylbiguanide (PBG), phenyldiguanide (PDG), phenylguanidine (PG) and 5-hydroxytryptamine (5-HT) have been investigated in the pentobarbitone-anaesthetized rabbit. The rank order of potency was 5-HT greater than PBG greater than PG greater than PDG. The responses evoked by all agonists were antagonized by pre-treatment with the selective 5-HT3 receptor antagonist MDL 72222, suggesting that their reflex effects are mediated by 5-HT3 receptors located on pulmonary vagal afferents. Furthermore, considering the low potency and long injection response time of PDG compared to PBG, we conclude that previous workers have used PBG and not PDG to identify non-myelinated pulmonary vagal afferents and to evoke the pulmonary chemoreflex.
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PMID:Phenylbiguanide not phenyldiguanide is used to evoke the pulmonary chemoreflex in anaesthetized rabbits. 235 May 16

Several 5-hydroxytryptamine (5-HT3) receptor antagonists have been described. In addition to 5-HT3 receptor antagonist activity, many of these agents also possess gastroprokinetic activity. In the present report, we identify compound LY277359 maleate as a potent, p.o. active, highly selective 5-HT3 receptor antagonist lacking gastroprokinetic effects. LY277359 maleate was a potent and selective antagonist of 2-methyl 5-HT-induced contraction in the guinea pig ileum (KB = 1.6 nM), a response mediated by activation of 5-HT3 receptors. Given both i.v. (0.0003, 0.001 and 0.003 mg/kg) and p.o. (0.01 and 0.03 mg/kg), LY277359 maleate inhibited the bradycardic response to i.v. administered 5-HT in urethane-anesthetized rats. The duration of antagonism of 5-HT-induced bradycardia persisted beyond 6 hr after p.o. administration of LY277359 maleate (0.03 mg/kg p.o.). In contrast to its potent 5-HT3 receptor antagonist activity, LY277359 maleate, in doses up to 1 mg/kg p.o., did not affect gastric emptying in rats, suggesting minimal, if any, gastroprokinetic activity of LY277359 maleate. This is in contrast to another 5-HT3 receptor antagonist, zacopride, which did produce a marked increase in gastric emptying in rats at doses of 0.1 mg/kg p.o. and higher. LY277359 maleate (0.03 and 0.1 mg/kg i.v. and 0.07, 0.1, 0.3 and 1.0 mg/kg p.o.) did have effects consistent with other 5-HT3 antagonists, to inhibit cisplatin-evoked emesis in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:LY277359 maleate: a potent and selective 5-HT3 receptor antagonist without gastroprokinetic activity. 236 87

A 5-hydroxytryptamine 5-HT3 receptor binding site has been purified from deoxycholate-solubilized NCB20 cell membranes. Purification (1,700-fold) was achieved in one step by affinity chromatography with L-685,603 immobilized on agarose. The 5-HT3 selective antagonist [3H]Q ICS 205-930 labeled a single population of receptors in the affinity-purified preparation with a Bmax of 3.1 +/- 0.9 nmol/mg protein and Kd of 0.40 +/- 0.05 nM (mean +/- S.E., n = 3). The rank order of potency for a series of competing compounds confirmed that [3H]Q ICS 205,930 was labeling a 5-HT3 receptor in the purified preparation, and the inhibition constants for all antagonists were unchanged after purification. The purified 5-HT3 binding site eluted from a Sepharose 6B gel filtration column in a similar manner to the crude solubilized preparation (Stokes radius of 4.9 nm, apparent molecular size 250,000). Polyacrylamide gel electrophoresis of the affinity-purified receptor showed two broad bands by silver staining, migrating with apparent molecular masses of 54,000 and 38,000. Gel filtration of the affinity purified material yielded a single peak labeled by [3H]Q ICS 205-930 with an apparent molecular size of 250,000, which was also composed of two bands of 54,000 and 38,000, consistent with these being the constituents of the 5-HT3 receptor.
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PMID:Purification of the 5-hydroxytryptamine 5-HT3 receptor from NCB20 cells. 238 Jan 74

The effects of 5-hydroxytryptamine (5-HT), the 5-HT1-like receptor agonist 5-carboxamidotryptamine and the 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine were studied on circular muscle strips of the canine terminal ileum and ileocolonic junction. Serial administration of 5-HT or of 5-carboxamidotryptamine induced slow tonic contractions that at higher concentrations of 5-HT (10(-4)-3 x 10(-4] were preceded by an initial relaxation and a fast phasic contraction. The concentration-response curves to both agonists were competitively shifted to the right by the mixed 5-HT1/5-HT2 receptor antagonist methysergide. The initial relaxation and fast phasic contraction were inhibited by the 5-HT3 receptor antagonist ICS 205-930 and tetrodotoxin. Atropine blocked the fast phasic contraction, but enhanced the relaxation. During acetylcholine-induced contractions, 5-HT and 2-methyl-5-hydroxytryptamine (greater than or equal to 10(-5) M), but not 5-carboxamidotryptamine, evoked relaxations that were blocked by ICS 205-930 and tetrodotoxin, but not by adrenoceptor antagonists. Thus, in the canine terminal ileum and ileocolonic junction, 5-HT stimulates neuronal 5-HT3 receptors and excitatory 5-HT1-like receptors located on smooth muscle. Stimulation of the 5-HT3 receptors results in an acetylcholine-mediated contraction and a relaxation mediated by an as yet unknown nonadrenergic noncholinergic neurotransmitter.
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PMID:Pharmacological characterization of 5-hydroxytryptamine receptors in the canine terminal ileum and ileocolonic junction. 238 90

GR67330 potently inhibited 5-hydroxytryptamine (5-HT)-induced depolarizations of the rat isolated vagus nerve. At the higher concentrations used (0.3 nmol/l-1 nmol/l) this was accompanied by a marked reduction in the maximum response to 5-HT. The calculated pKB value was 10.2. The binding of the tritiated derivative of GR67330 to homogenates of rat entorhinal cortex was examined. Kinetic analysis revealed that specific [3H] GR67330 (0.1 nmol/l) binding was rapid and reversible. Association and dissociation rate constants were 1.48 +/- 0.36 x 10(8) mol/l-1 s-1 and 7.85 +/- 0.41 x 10(-3) s-1 respectively. Equilibrium saturation analysis revealed specific binding was to a single site (Bmax 22.6 +/- 0.21 fmol/mg protein) of high affinity (Kd 0.038 +/- 0.003 nmol/l). At low ligand concentrations, specific binding was up to 90% of total binding. If unlabelled GR67330 was used to define non-specific binding two sites were evident (Kd1 0.066 +/- 0.007 nmol/l, Kd2 20.1 +/- 9.7 nmol/l; Bmax1 31.5 +/- 3.2 fmol/mg protein, Bmax2 1110 +/- 420 fmol/mg protein). [3H] GR67330 binding was inhibited potently by 5-HT3 antagonists and agonists. Ligands for other 5-HT receptors and other neurotransmitter receptors were either only weakly active or inactive at inhibiting binding. Hill numbers for antagonist inhibition of binding were close to unity, except for quipazine which was significantly greater than one. In common with other 5-HT3 binding studies, all 5-H-agonist tested had Hill numbers greater than one (1.51-1.71). GR38032 and GR65630 inhibited a greater proportion of binding than other 5-HT3 antagonists, this additional binding was interpreted as inhibition from a second saturable site unrelated to the 5-HT3 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[3H] GR67330, a very high affinity ligand for 5-HT3 receptors. 240 1

Agonist-induced desensitization has been utilized to discriminate and independently "isolate" the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT3 and putative 5-HT4 receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mumol/l) inhibited completely responses to 5-HT at the putative 5-HT4 receptor without affecting 5-HT3-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mumol/l) inhibited completely responses to 5-HT at the 5-HT3 receptor without affecting putative 5-HT4-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCl, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA2 values for ICS 205-930 at the putative 5-HT4 (pA2 = 6.2 to 6.5) and 5-HT3 (pA2 = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5-HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization. 5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT4 receptor. It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT4 receptor from the 5-HT3 receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT4 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum. 240 3

The neurohormone 5-hydroxytryptamine (5HT or serotonin) exerts its effects by binding to several distinct receptors. One of these is the M-receptor of Gaddum and Picarelli, now called the 5-HT3 receptor, through which 5-HT acts to excite enteric neurons. Ligand-binding and functional studies have shown that the 5-HT3 receptor is widely distributed in peripheral and central nervous tissue and evidence suggests that the receptor might incorporate an ion channel permeable to cations. We now report the first recordings of currents through single ion channels activated by 5-HT3 receptors, in excised (outside-out) membrane patches from neurons of the guinea pig submucous plexus. Whereas application of acetylcholine activated predominantly a 40-pS channel, 5-HT caused unitary currents apparently through two channels of conductances of 15 and 9 pS, which were reversibly blocked by antagonists of the 5-HT3 receptor. Receptors for amine neurotransmitters, including 5-HT1 and 5-HT2, have previously been thought to transduce their effects through GTP-binding proteins: the direct demonstration that 5-HT3 receptors are ligand-gated ion channels implies a role for 5-HT, and perhaps other amines, as a 'fast' synaptic transmitter.
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PMID:5-HT3 receptors are membrane ion channels. 247 53

Flat sheet preparations of the mucosa plus submucosa from the guinea-pig ileum were placed in Ussing chambers so that short circuit current (Isc), an index of electrolyte movement across the mucosa, could be measured. In these preparations, 5-hydroxytryptamine (5-HT) increases Isc indirectly by stimulating both cholinergic and non-cholinergic secretomotor neurons. The 5-HT3 receptor antagonist, ICS 205-930 (10(-13)-10(-5 M), substantially depressed the secretory response due to 5-HT (10(-6) M), but not that produced by direct activation of muscarinic receptors on the mucosal epithelium with carbachol (10(-6) M), or by stimulation of secretomotor neurons with substance P (10(-8) M) or 1,1-dimethyl-4-phenylpiperazinium (10(-5)M). The residual response to 5-HT, after the addition of a maximally effective concentration of ICS 205-930 (10(-6) M), was further reduced by hyoscine (10(-7) M). When that part of the 5-HT response attributable to the release of acetylcholine was blocked by hyoscine (10(-7) M), ICS 205-930 did not further modify the response to 5-HT. The hyoscine-resistant component was, however, substantially depressed by tetrodotoxin (3.5 x 10(-7) M). The response remaining after ICS 205-930 and hyoscine was not affected by methysergide (2 x 10(-5) M) or cyproheptadine (10(-7) M). We conclude that there are ICS 205-930 sensitive 5-HT receptors on cholinergic secretomotor neurons, and ICS 205-930, methysergide, and cyproheptadine insensitive 5-HT receptors on non-cholinergic secretomotor neurons.
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PMID:Evidence for two types of 5-hydroxytryptamine receptor on secretomotor neurons of the guinea-pig ileum. 247 54

1. Ionic currents mediated by serotonin 5-HT3 receptors were studied in the mouse neuroblastoma cell line N1E-115, using suction pipettes for intracellular perfusion and voltage clamp recording. The dependence of the kinetics of the membrane current on serotonin concentration was investigated. 2. At a holding potential of -70 mV application of 5-HT (5-hydroxytryptamine creatinine sulphate) causes a transient inward current. The i-V curve of the peak amplitude is linear between -80 and 60 mV. The reversal potential is 20 +/- 4 mV (mean +/- S.D.). The kinetics of the transient ionic current are independent of the holding potential. 3. In the presence of 5-HT the membrane current decays to a small steady-state level with a single-exponential time course. The time constant of decay decreases with increasing concentration of the agonist, to a minimum value of 6.5 +/- 1.5 s for concentrations of 5-HT greater than or equal to 3 microM. 4. When the agonist is rapidly removed, single-exponential decay of the ionic current is observed. The time constant of this decay in the absence of 5-HT amounts to 6.9 +/- 1.5 s and is independent of the membrane potential and of the concentration of 5-HT used. 5. In the presence of low concentrations of 5-HT the peak amplitude of the inward current evoked with a high concentration of agonist is gradually reduced. The onset of this desensitization follows the same time course as the decay of the membrane current. In the range from 0.7 to 1.5 microM-5-HT both kinetic processes show the same steep concentration dependence. 6. Recovery from desensitization, measured at variable intervals after removal of the agonist, can be fitted by a single-exponential function with a time constant of 18 +/- 4 s. 7. The results show that the kinetic properties of the 5-HT3 receptor-mediated ionic current can only be described by a complex, co-operative model.
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PMID:Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells. 248 54

1. The cerebral topography of the action of diazepam and the action of the 5-hydroxytryptamine 5-HT3 receptor antagonists GR38032F and ICS 205-930 in attenuating an aversive response was studied in the mouse. 2. Mice which had been cannulated to allow drug injection into the dorsal and median raphe nuclei, the amygdala, nucleus accumbens or caudate-putamen were placed in a two compartment black (dimly illuminated) and white (brightly illuminated) test box. Measurements were made of the time spent, rearing and line crossings in the two sections and the latency of initial movement from the white to the black area. 3. The injection of diazepam (0.1-10 ng), GR38032F (0.01-1.0 ng) and ICS 205-930 (1.0-10 ng) into the dorsal raphe nucleus and amygdala, and the injection of diazepam (0.1-10 ng) into the median raphe nucleus, reduced an aversive response to the brightly illuminated white area, delaying the initial movement into the black section and increasing the time spent, rearings and line crossings in the white area. Concomitantly such activities were decreased in the black section. 4. The injection of the 5-HT3 agonist 2-methyl-5-hydroxytryptamine (0.1-10 ng) into the dorsal raphe nucleus and amygdala caused the opposite response, decreasing the time taken to move into the black section and increasing the time spent, rearings and line crossings in the black section, decreasing such activities in the white area. 5. The 5-HT3 agonist and antagonists showed little or no effect following injection into the median raphe nucleus and there were no changes in exploratory behaviour following their injection, or injection of diazepam, into the nucleus accumbens or caudate-putamen. 6. It is concluded that in the mouse the cerebral topography of action of GR38032F and ICS 205-930 in attenuating an aversive response follows that of diazepam in the dorsal raphe nucleus and amygdala but that diazepam may have additional effects mediated via the median raphe nucleus.
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PMID:Neuroanatomical sites of action of 5-HT3 receptor agonist and antagonists for alteration of aversive behaviour in the mouse. 252 35


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